Summary of Work: The stability of genomes, particularly humans, is influenced by opportunities for recombination between long (0.3 -10 kb) repeats of diverged DNAs such as ALUs and LINES, rearrangements between very short (4-10 bp) random repeats and replication slippage within the stretches of microsatellites. All these repeats are abundant in the genome. Homonucleotide runs and other microsatellites are a source of frequent replication slippage leading to frameshift mutations inactivating genes. We have demonstrated that unpaired loops resulting from replication slippage in long homonucleotide runs are not subject to proofreading by the DNA polymerase 3' to 5' exonuclease, because they are distant to the 3'-terminus of the nascent strand. As a result, the prevention of mutations would rely primarily on postreplication mismatch repair. This has now been demonstrated by the hypermutability (as much as 10,000-fold) of homonucleotide runs and other microsatellites in mismatch repair deficient cells. We have determined that a mismatch repair defect renders genes with a long homonucleotide run 100-fold more mutable than genes lacking homonucleotide runs in the coding sequence. Thus, homonucleotide runs represent important at-risk sequences in the genome and could be an important source of human disease.